Spinal muscular atrophy (SMA) is a currently untreatable, autosomal recessive genetic disease caused by a deficiency of full-length survival motor neuron (SMN) protein. The symptoms are the result of progressive degeneration of motor neurons in the anterior horn of the spinal cord resulting in weakness and wasting of the voluntary muscles.
Type I (Acute) SMA is also called Werdnig-Hoffmann Disease. SMA type I is evident before birth or within the first few months of life. There may be a reduction in fetal movement in the final months of pregnancy. There is a general weakness in the intercostals and accessory respiratory muscles. The chest may appear concave. Symptoms include floppiness of the limbs and trunk, feeble movements of the arms and legs, swallowing and feeding difficulties, and impaired breathing. Affected children never sit or stand and usually die before the age of 2.
Type II (Chronic) SMA is usually diagnosed by 15 months. Children may have respiratory problems, floppy limbs, decreased or absent deep tendon reflexes, and twitching of arm, leg, or tongue muscles. These children may learn to sit but cannot stand or walk. Life expectancy varies. Feeding and swallowing problems are not usually characteristic of Type II, although in some patients a feeding tube may become necessary. Tongue fasciculations are less often found in children with Type II but a fine tremor in the outstretched fingers is common.
Type III (Mild) SMA, often referred to as Kugelberg-Welander or Juvenile Spinal Muscular Atrophy, is usually diagnosed between 2 and 17 years of age. Symptoms include abnormal manner of walking; difficulty running, climbing steps, or rising from a chair; and slight tremor of the fingers. The patient with Type III can stand alone and walk; tongue fasciculations are seldom seen. Types I, II and III progress over time, accompanied by deterioration of the patient's condition.
Type IV (Adult Onset) typically begins after age 35. Adult SMA is characterized by insidious onset and very slow progression. The bulbar muscles are rarely affected in Type IV. It is not clear that Type IV SMA is etiologically related to the Type I-III forms. There is a second type of Adult Onset X-Linked SMA, known as Kennedy's Syndrome or Bulbo-Spinal Muscular Atrophy. It occurs only in males, and, unlike the other forms of SMA, it is associated with a mutation in the gene that codes for part of the androgen receptor. The facial and tongue muscles are noticeably affected. The course of the Adult Onset disease is variable, but in general it tends to be slowly progressive or nonprogressive.
Type I, II and III SMA are caused by a mutation in a part of the DNA called the survival motor neuron (SMN1) gene, which normally produces a protein called SMN. Because of their gene mutation, people with SMA make less SMN protein, which results in the loss of motor neurons. SMA symptoms may be improved by increasing the levels of SMN protein. Normally the SMN1 gene provides instructions for making a protein called Survival of Motor Neuron 1. The SMN1 protein helps to assemble the cellular machinery needed to process pre-mRNA. More than 90 percent of individuals with spinal muscular atrophy lack part or all of both copies of the SMN1 gene. A small percentage of people with this condition lack one copy of the SMN1 gene and have a small type of mutation in the remaining copy. About 30 different mutations have been identified. The most frequent of these mutations replaces the amino acid tyrosine with cysteine at position 272 in the SMN1 protein. Other mutations replace amino acids at different positions or produce an abnormally short protein. As a result of these missing or altered genes, cells have a shortage of functional SMN1 protein. It remains unclear why motor neurons are particularly vulnerable to a shortage of this protein. Loss of the SMN1 protein from motor neurons results in the degeneration of these nerve cells, leading to the signs and symptoms of spinal muscular atrophy.
In some cases of spinal muscular atrophy, particularly the milder cases, the SMN1 gene is replaced by an almost identical gene called SMN2. Typically, people who do not have spinal muscular atrophy have two copies of the SMN2 gene. In some affected individuals, however, the SMN2 gene replaces the SMN1 gene, and as a result, the number of SMN2 genes increases from two to three or more (and the number of SMN1 genes decreases). On a limited basis, extra SMN2 genes can help replace the protein needed for the survival of motor neurons. In general, symptoms are less severe and begin later in life in affected individuals with three or more copies of the SMN2 gene. The SMN2 gene provides instructions for making a protein called survival of motor neuron 2. This protein is made in four different versions, but only isoform d is full size and functional and appears to be identical to the SMN1 protein. The other isoforms (a, b, and c) are smaller and may not be fully functional. It appears that only a small amount of the protein made by the SMN2 gene is isoform d. Among individuals with spinal muscular atrophy (who lack functional SMN1 genes), additional copies of the SMN2 gene can modify the course of the disorder. On a limited basis, the extra SMN2 genes can help replace the protein needed for the survival of motor neurons. Spinal muscular atrophy still occurs, however, because most of the proteins produced by SMN2 genes are isoforms a, b, and c, which are smaller than the SMN1 protein and cannot fully compensate for the loss of SMN1 genes. A recent article by Cartegni and Krainer [Nature Genetics 30, 377-384 (2002)] suggests that the molecular basis for the failure of the nearly identical gene SMN2 to provide full protection against SMA stems from inefficient recognition of an exonic splicing enhancer by the splicing factor SF2/ASF. Even so, the small amount of full-sized protein produced from three or more copies of the SMN2 gene can delay onset and produce less severe symptoms, as seen in spinal muscular atrophy, types II and III.
One of the first studies on pharmaceutical therapy for spinal muscular atrophy has demonstrated that, in cultured cells, valproic acid increases production of normal protein produced by the SMN2 gene. While preliminary, these studies [Britcha et al. Human Molecular Genetics, 12, 2481-2489 (2003); Sumner et al. Annals of Neurology, 54, 647-654 (2003)], suggest that valproic acid or related drugs may be able to halt or even reverse the course of SMA. The study used cultured cells taken from patients with SMA type I, and demonstrated a dose-related increase in gene activity, increasing production of functional SMN protein by 30 to 50 percent. Unfortunately, treatment with valproic acid can lead to liver toxicity, especially in children under 2 years of age, and safe doses of the drug may not be able to increase the amount of SMN protein enough to reduce symptoms of the disease. However, valproic acid belongs to a class of drugs known as histone deacetylase (HDAC) inhibitors, and persons of skill in the art believe that other HDAC inhibitors may be useful for treating SMA. For example, two other HDAC inhibitor, sodium butyrate and phenylbuytreate have also been shown to increase SMN expession [Chang et al. PNAS, 98, 9808-9813 (2001); Andreassi et al. European Journal of Human Genetics, 12, 59-65. The National Institute of Neurological Disorders and Stroke (NINDS) is currently undertaking studies to support this hypothesis.
It would be useful to have compounds that promote SMN2 without the adverse side effects of valproic acid. It would be further useful to have compounds that increase the total SMN1 protein or that alter the splicing to provide increase in Full length to Δ7 SMN transcripts ratio in favor of full length protein or that do both.